Project 1: Decoding Origin and Modeling Oncohistones in Pediatric Cancers

项目 1：解码儿科癌症中的癌组蛋白起源并对其进行建模

• 批准号: 9142305
• 负责人: NADA JABADO
• 金额: $ 28.29万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9142305
• 关键词: 20 year old; Address; Affect; Age; Anatomy; Animal Model; Area; Astrocytoma; Autopsy; Biological Models; Biology; Biopsy; Bone neoplasms; Brain; Brain Mapping; Brain Neoplasms; CRISPR/Cas technology; Cell Line; Cells; Cerebral hemisphere; ChIP-seq; Child; Childhood; Chondroblastoma; Chromatin; Chromatin Structure; Clinical; Collaborations; Complex; DAXX gene; DNA Sequence Alteration; DNA Sequencing Facility; Data; Data Set; Defect; Deposition; Development; Diagnosis; Disease; Ensure; Epigenetic Process; Experimental Models; Frequencies; Funding; Future; Genes; Genetic Transcription; Genome; Genomics; Giant Cell Tumors; Growth Factor Receptors; Growth and Development function; Harvest; Histones; Human; Investigation; Knock-in; Knowledge; Label; Lead; Learning; Link; Location; LoxP-flanked allele; Maintenance; Malignant Bone Neoplasm; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Measurement; Mesenchymal Stem Cells; Methylation; MicroRNAs; Modeling; Monitor; Mus; Mutant Strains Mice; Mutation; Normal tissue morphology; Organ; Organ Specificity; PRC1 Protein; Patient Care; Patients; Pattern; Positioning Attribute; Primary Neoplasm; Protein Isoforms; Proteins; Proteomics; Recurrence; Relapse; Research Personnel; Resource Sharing; Resources; Role; Sampling; Site; Specificity; Staging; TP53 gene; Technology; Tissues; Translating; Tumor Cell Line; Variant; Xenograft procedure; age group; aging brain; bisulfite sequencing; bone; chromatin remodeling; design; effective therapy; epigenetic regulation; epigenome; epigenomics; gain of function; genetic information; genome editing; human disease; improved; insight; mouse model; mutant; novel; organ growth; programs; tool; transcriptome; tumor; tumor heterogeneity; tumorigenesis; tumorigenic; whole genome; young adult; zinc finger nuclease

PROJECT SUMMARY We and others recently identified mutations in histone 3 variants in a significant fraction of children and young adults with a deadly brain tumor and maiming bone cancers. This is a very new uncharted area in cancer that will benefit from improved understanding of disease biology and the design of accurate experimental models to recapitulate these epigenetic cancers as we aim to do in this project. Strikingly data we further acquired with other funding suggest these “oncohistones” as we labeled them possibly arise during specific windows of normal organ development. Indeed, each mutation in a given H3 isoform has age, organ and anatomic location within an organ, specificities. There is added complexity in HGA as we showed requirement of distinct added genetic alterations that are also age, brain location and H3 variant specific. Oncohistones are a new major paradigm shift in the field of cancer, and limited knowledge exists on how they act in tumor formation. Our project, integrated with other projects in this Program, aims to overcome this major knowledge gap and obstacle to effective therapy. We aim to “decode” how these mutations mechanistically affect the epigenomic landscape in tumors in the context of Development (Aims 1 and 2). We will provide critically needed relevant experimental models of histone mutations (Aim 2) and thrive to faithfully recapitulate human disease in HGA (Aims 2 and 3). Our group (Jabado/Majewski) was one of two to first identify a histone mutation in human disease. We have first-hand knowledge on HGA and other pediatric cancers and unparalleled access to tumor samples, animal models and clinical information. Allis identified H3.3 and the Allis and Muir labs are one of the best positioned to biochemically and mechanistically help study these mutations. There is natural synergy, cross-interactions and sharing of resources and materials between the three projects in this Program. We will receive essential support to integrate and analyse the vast datasets we are generating in primary tumors and model systems while benefiting from the resources and novel technical approaches and integration of complex datasets used by the Genomics/Epigenomics Sequencing core (Majewski and the epigenomic expert co- investigator Pastinen). The Quantitative proteomics core (Garcia), one of the rare groups able to study combination of mutations in histones on the protein level will allow precise measurement of histone mutants in patients and mouse samples and our experimental models. The natural interactions and synergies within this program and the level of expertise within it ensure that we will make significant breakthroughs in these cancers that can translate into improved care for patients.

项目摘要 我们和其他人最近确定了大量儿童和年轻人的组蛋白3变体突变 成年人患有致命的脑肿瘤和残疾骨癌。这是一个非常新的癌症领域 将受益于对疾病生物学的了解以及精确实验模型的设计的受益 像我们在该项目中要做的那样，概括了这些表观遗传癌。我们进一步获取了惊人的数据 其他资金表明，当我们标记它们可能会在特定窗户的特定窗户中出现时，这些“饮料酮” 正常器官发育。实际上，给定的H3同工型中的每个突变都有年龄，器官和解剖位置 在器官中，特殊性。正如我们所表明的不同添加的要求，HGA中还增加了复杂性 年龄，大脑位置和H3变体特异性的遗传改变。关于酒精酮是一个新的专业 癌症领域的范式转移，并且有关它们在肿瘤形成中的作用的知识有限。我们的 与该计划中其他项目集成的项目旨在克服这一主要知识差距和 有效治疗的障碍。我们的目标是“解码”这些突变如何机械地影响表观基因组学 在发育的背景下，肿瘤中的景观（目标1和2）。我们将提供迫切需要的相关 组蛋白突变的实验模型（AIM 2），并蓬勃发展，忠实地概括了HGA中的人类疾病 （目标2和3）。我们的小组（Jabado/Majewski）是首先确定人类的Hisstone突变之一 疾病。我们有关于HGA和其他儿科癌症的第一手知识，并且无与伦比地进入肿瘤 样品，动物模型和临床信息。 Allis确定了H3.3，而Allis和Muir Labs是之一 最适合生化和机械帮助研究这些突变的位置。有天然协同作用， 该计划中三个项目之间的交叉互动和资源和材料共享。我们将 获得基本的支持，以整合和分析我们在原发性肿瘤中生成的庞大数据集和 模型系统同时受益于资源和新颖的技术方法和复杂的集成 基因组/表观基因组学测序核心使用的数据集（Majewski和表观基因组专家共同 研究人员Pastinen）。定量蛋白质组学核心（GARCIA），能够研究的稀有群体之一 组蛋白在蛋白质水平上突变的组合将允许精确测量组蛋白突变体中的组蛋白突变体 患者和小鼠样品以及我们的实验模型。其中的自然互动和协同作用 计划和其中的专业知识水平确保我们将在这些取消中取得重大突破 这可以转化为患者的改善护理。